Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors can be divided into two classes which act through distinct signal transduction pathways. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases, and the second class, including thrombin, bombesin, bradykinin and vasopressin activates a phosphoinositide-specific phospholipase C through GTP-binding proteins which can be inactivated by pertussis toxin. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin. Thrombin, like the other mitogens in this class, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (Gi), a well established pertussis toxin substrate. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent and mitogen for smooth muscle cells, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT2 receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT1B receptor. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by Gi is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.
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PMID:Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. 304 68

BC3H-1 myocytes contain a phospholipid(s) which is labeled with [3H]inositol, [3H]glucosamine, and [3H]myristate [a phosphatidylinositol-glycan (PI-glycan)], and which is hydrolyzed by insulin induced activation of a specific phospholipase C. Similarly, epidermal growth factor and insulin-like growth factor-I provoke rapid increases in the hydrolysis of this PI-glycan, suggesting that derived signaling substances may be important in the action of agonists which activate tyrosine kinase type receptors.
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PMID:Epidermal growth factor and insulin-like growth factor I stimulate the hydrolysis of the insulin-sensitive phosphatidylinositol-glycan in BC3H-1 myocytes. 305 11

Isolated rat hepatocytes responded to a variety of Ca2+-mobilizing agents (vasopressin, angiotensin II, epinephrine, epidermal growth factor, ATP, and ADP) with a rapid increase in phosphatidate mass, as measured by a sensitive new method. When hepatocytes were incubated with vasopressin (10(-8) M), phosphatidate levels increased 2-3-fold in 2 min, but there was no significant increase in diacylglycerol at this time. Changes in the fatty acid composition of phosphatidate also preceded those in diacylglycerol. De novo synthesis of phosphatidate from [3H]glycerol was unaffected by vasopressin in short-term incubation. Incubation of washed rat liver plasma membranes with GTP gamma S caused a time-dependent increase in phosphatidate. When membranes were incubated with GTP gamma S and [gamma-32P]ATP, no incorporation of 32P into phosphatidate was observed. This excludes the phospholipase C-diacylglycerol kinase pathway and suggests that a phospholipase D activity produced the phosphatidate. At submaximal concentrations of GTP gamma S, ATP and ADP stimulated membrane phosphatidate formation, presumably by acting through P2-purinergic receptors. Only phosphatidylcholine, among the major phospholipids, decreased in the membranes in response to GTP gamma S. The fatty acid composition of the phosphatidate produced in response to vasopressin in hepatocytes also suggests that phosphatidylcholine may be the source of hormonally elicited phosphatidate. We conclude that Ca2+-mobilizing hormones mainly increase phosphatidate levels in hepatocytes by a mechanism that does not involve phosphorylation of diacylglycerol or de novo synthesis but involves a guanine nucleotide-binding protein coupled to phospholipase D.
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PMID:Phosphatidate accumulation in hormone-treated hepatocytes via a phospholipase D mechanism. 311 99

Tumor-promoting phorbol esters induce ornithine decarboxylase (ODCase) activity and reduce epidermal growth factor (EGF) binding in rat tracheal epithelial 2C5 cells. Phorbol esters activate protein kinase C by interacting at the same site as sn-1,2-diacylglycerols, the presumed physiological regulators. The effects of added sn-1,2-diacylglycerols and those generated by phospholipase C treatment of 2C5 cells on ODCase induction and EGF binding were investigated to establish a role for protein kinase C in these cellular responses. Treatment of 2C5 cells with phospholipase C induced ODCase activity and reduced EGF binding, whereas phospholipases A2 and D were inactive. When sn-1,2-diacylglycerols containing fatty acids 3-10 carbons in length were added to 2C5 cells, those diacylglycerols containing fatty acids 5-10 carbons in length caused ODCase induction and reduction in EGF binding. sn-1,2-Dioctanoylglycerol was one of the most active compounds tested. It induced ODCase in a dose- (50-500 microM) and time-dependent manner. The reduction of binding of 125I-labeled EGF by sn-1,2-dioctanoylglycerol was also time and dose dependent and appeared to result from a change in EGF affinity and not the number of receptor sites. This series of sn-1,2-diacylglycerols showed similar structure-function relationships in their ability to induce ODCase activity, to decrease EGF binding, to stimulate protein kinase C, and to inhibit [3H]phorbol dibutyrate binding to the phorbol ester receptor. These data demonstrate biological activities for a number of diacylglycerols and indicate that protein kinase C activation is implicated in ODCase induction and decreased EGF binding.
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PMID:Role of protein kinase C in diacylglycerol-mediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding. 315 91

Utilizing a digitonin-permeabilized cell system, we have studied the release of calcium from a non-mitochondrial intracellular compartment in cultured human fibroblasts (HSWP cells). Addition of 1 mM MgATP to a monolayer of permeabilized cells in a cytosolic media buffered to 150 nM Ca with EGTA rapidly stimulates 45Ca uptake, and the subsequent addition of the putative intracellular messenger inositol trisphosphate (InsP3) induces rapid release of 85% (+/- 6% n = 6) of the 45Ca taken up in response to ATP. Mitogenic peptides (bradykinin, vasopressin, epidermal growth factor [EGF], and insulin) and orthovanadate, which are effective in mobilizing intracellular Ca in intact cells, have little or no effect when added alone to permeabilized cells. However, in the presence of GTP these agents stimulate accumulation of inositol phosphates and release Ca from the InsP3-sensitive pool. These data suggest that a GTP binding protein is involved in receptor mediated activation of phospholipase C, which leads to release of inositol phosphates. The GTP-dependent release of InsP3 and the mobilization of 45Ca from the intracellular compartment are inhibited by pretreatment of cells, prior to permeabilization, with the protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). TPA pretreatment does not affect the InsP3 stimulated Ca release. These results suggest that protein kinase C is involved in down-regulation or inhibition of phospholipase C, or the GTP binding protein responsible for relaying the mitogenic signal from the cell surface receptor to the phospholipase C activity.
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PMID:Calcium mobilization in permeabilized fibroblasts: effects of inositol trisphosphate, orthovanadate, mitogens, phorbol ester, and guanosine triphosphate. 349 99

Staphylococcus aureus alpha-toxin, at sub-cytotoxic concentrations, inhibits both the 125I-labeled epidermal growth factor (EGF) binding and autophosphorylation properties of EGF-receptors in PC12 cells. This inhibition occurred only in intact cells and is probably due to a decrease in the affinity of the receptor for EGF. Streptolysin S and parcelsin could mimic the alpha-toxin effect below cytotoxic concentrations, as measured by a 51Cr release assay. In contrast, other membrane perturbing toxins with different lipid specificity, such as tetanolysin and cobra direct lytic factor, inhibited [125I]EGF binding only at cytotoxic concentrations. Staphylococcal alpha-toxin also stimulated 3-fold the specific binding of a radioactive tumor-promoting phorbol ester (PDBu) to PC12 cells at concentrations similar to those required for the inhibition of [125I]EGF binding. Although the exact mechanism for the inhibition of EGF binding by alpha-toxin has not been established, our results suggest that protein kinase C may be involved in this time-dependent process.
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PMID:Staphylococcus aureus alpha-toxin. 2. Reduction of epidermal growth factor receptor affinity in PC12 cells. 349 39

The ability of epidermal growth factor (EGF) and angiotensin II to stimulate production of inositol trisphosphate and mobilize intracellular Ca2+ in hepatocytes was compared using quin2 fluorescence to monitor changes in Ca2+ levels and high performance liquid chromatography to resolve the inositol trisphosphate (InsP3) isomers. Both EGF and angiotensin II stimulated an increase in free intracellular Ca2+ concentration ([Ca2+]i) as well as a rapid increase in the production of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Concentrations of angiotensin II which gave a rise in [Ca2+]i equivalent to that seen with maximal doses of EGF produced an equivalent increase in Ins(1,4,5)P3 formation. Both EGF and angiotensin II stimulated the formation of the Ins(1,3,4)P3 and inositol 1,3,4,5-tetrakisphosphate isomers. The formation of the Ins(1,3,4)P3 isomer lagged behind production of Ins(1,4,5)P3 but eventually reached higher levels in the cell. The initial rise in [Ca2+]i and InsP3 levels stimulated by EGF and angiotensin II was not affected by reducing the external Ca2+ concentration below 30 nM with an excess of [ethylenebis(oxyethylenenitrilo)] tetraacetic acid. Treatment of hepatocytes for 30-180 s with 1 micrograms/ml phorbol 12-myristate 13-acetate prior to the addition of EGF blocked the EGF-stimulated production of Ins(1,4,5)P3 and the increase in [Ca2+]i. Phorbol 12-myristate 13-acetate attenuated the production of Ins(1,4,5)P3 generated by angiotensin II over the concentration range of 10(-10) to 10(-8) M; however, the Ca2+ signal was only inhibited at the 10(-10) M dose of angiotensin II. Treatment of rats with pertussis toxin for 72 h prior to isolating hepatocytes blocked the ability of EGF to increase Ins(1,4,5)P3 and Ins(1,3,4)P3 but did not inhibit the ability of any concentration of angiotensin II to stimulate formation of InsP3 or inositol tetrakisphosphate. The observation that pertussis toxin selectively abolishes EGF-stimulated inositol lipid breakdown suggests that EGF and angiotensin II use different mechanisms to activate phospholipase C in hepatocytes.
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PMID:Epidermal growth factor and angiotensin II stimulate formation of inositol 1,4,5- and inositol 1,3,4-trisphosphate in hepatocytes. Differential inhibition by pertussis toxin and phorbol 12-myristate 13-acetate. 350 Sep 49

Interaction of tumor promoting phorbol esters with specific high affinity receptors is probably essential for many of the biological responses elicited by these agents. Since diacylglycerols which can be produced enzymatically from phospholipids by phospholipase C are postulated to be the physiological ligands for the phorbol ester receptor, we have examined primary cultures of mouse epidermal basal cells exposed to phospholipase C (Clostridium perfringens) for several biological and biochemical responses characteristic of treatment with 12-O-tetradecanoyl-phorbol-13-acetate, the most potent phorbol ester tumor promoter. Formation of diacylglycerols by treatment with phospholipase C was demonstrated by the dose-dependent release of radioactive diacylglycerols in cells prelabeled with [3H]arachidonic acid. Treatment with phospholipase C at 0.05 units/ml for 30 min led to the morphological changes and to the reduction in epidermal growth factor binding (90%) associated with 12-O-tetradecanoylphorbol-13-acetate treatment. Continuous treatment at the same dose led to the induction of the enzymes ornithine decarboxylase and transglutaminase with a time course and extent similar to the inductions by 12-O-tetradecanoylphorbol-13-acetate. Treatment with phospholipase C at 0.1 enzyme unit/ml yielded substantial suppression of the binding affinity of phorbol-12,13-dibutyrate for its receptors without reduction in total number of binding sites, consistent with the production by phospholipase C of a competitive inhibitor of phorbol ester binding. Several diacylglycerols at concentrations of 250 microM and above effectively competed for phorbol-12,13-dibutyrate binding, reduced epidermal growth factor binding, and to a lesser extent induced ornithine decarboxylase and transglutaminase. These results support the hypothesis that diacylglycerols can act through the phorbol ester receptors and thus produce biological and biochemical responses similar to those of the phorbol esters.
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PMID:Similar effects of phospholipase C and phorbol ester tumor promoters on primary mouse epidermal cells. 393 7

The purpose of these studies was to determine whether increased cellular diacylglycerol could modulate phorbol ester receptor properties, in order to demonstrate that diacylglycerol can interact with and modulate the phorbol ester receptor in intact cells. Treatment of GH4C1 cells with bacterial phospholipase C caused an increase in cellular diacylglycerol. This was accompanied by increased PRL secretion and decreased epidermal growth factor (EGF) binding, two responses that also occur with phorbol ester treatment of GH4C1 cells. Phospholipase C treatment led to decreased apparent affinity for phorbol esters with no change in receptor number when measured in intact cells. This is consistent with increased concentrations of a competitive inhibitor of phorbol ester binding in treated cultures. Phospholipase C treatment caused a change in subcellular distribution of phorbol ester receptors, another response characteristic of phorbol ester treatment. TRH is known to activate endogenous phospholipase C activity in these cells, leading to a transient increase in diacylglycerol levels. TRH treatment also led to a transient change in subcellular distribution of phorbol ester receptors. In addition, a coordinate change in subcellular distribution of protein kinase C was observed. These data suggest that diacylglycerol is an endogenous ligand for the target for phorbol ester action in GH4C1 cells.
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PMID:Increased diacylglycerol content with phospholipase C or hormone treatment: inhibition of phorbol ester binding and induction of phorbol ester-like biological responses. 393 61

We recently showed that epidermal growth factor (EGF) inhibits cholecystokinin-octapeptide (CCK-8)-induced activation of phospholipase C and amylase release in isolated rat pancreatic acini. In the present study the effect of EGF on amylase release and inositol 1,4,5-trisphosphate (1,4,5-IP3) production in response to other calcium-mobilizing secretagogues, i.e. bombesin and carbachol, was examined in isolated pancreatic acini. EGF (17 nM) inhibited bombesin (100 nM)-stimulated amylase secretion from 10.3 +/- 1.7% to 0.8 +/- 1.6% of total above basal. Different from CCK-8, EGF reduced amylase release at both submaximal (< or = 1 microM) and supramaximal (> 1 microM) carbachol concentrations. Moreover, EGF (17 nM) inhibited bombesin-, carbachol-, and CCK-8-induced 1,4,5-IP3-production at five seconds after beginning of the incubation by 81 +/- 19%, 65 +/- 15%, and 60 +/- 12%, respectively. In conclusion, these results show that EGF inhibits amylase secretion in response to diverse calcium-mobilizing secretagogues in the exocrine pancreas and suggests that this inhibition is mediated by inhibition of phospholipase C.
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PMID:Epidermal growth factor inhibits amylase secretion and activation of phospholipase C in response to calcium-mobilizing secretagogues in rat pancreatic acini. 751 89


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